Pharmacology - An Illustrated Review

Questions & Answers

Review Questions

1. What is the term used to describe the fraction of a drug dose that reaches the systemic circulation?

A.   Plasma half-life

B.   Bioavailability

C.   Enterohepatic cycling

D.   Biotransformation

E.   Biliary excretion

2. A new antiarrhythmic agent is given intravenously to a patient with premature ventricular contractions in a dose of 500 mg. The electrocardiogram (ECG) is monitored, and blood samples are taken for analysis of plasma concentrations. The following concentrations were reported from the laboratory (see table, below). The ECG tracing showed changes in myocardial conduction for 30 minutes after administration that were indicative of the toxic effect of the drug. The patient's premature ventricular contractions were not apparent on the ECG until 5 hours after the drug was given intravenously. The information from the drug company contains no data on the metabolism or renal clearance of the drug. The patient has no preexisting liver or kidney disease. What is the apparent volume of distribution (Vd) of the drug?

Time after Administration (hours)

Concentration of Free Drug (µg/mL)

0.5

4.5

1

4.0

2

3.4

3

2.8

4

2.4

5

2.0

6

1.7

7

1.4

8

1.3

A.   40 L

B.   100 L

C.   200 L

D.   400 L

3. The patient in question is sent home with an oral preparation of the drug. You have decided to maintain the average plasma concentration halfway between the toxic and minimal therapeutic plasma concentrations and to give the drug every 8 hours. What would be the dose within 50 mg that the patient would take?

A.   100 mg

B.   200 mg

C.   350 mg

D.   800 mg

E.   1 g

4. A patient who has been taking secobarbital (a barbiturate that induces the liver microsomal enzyme system) for several weeks is stabilized on warfarin (an oral anticoagulant that is inactivated by side-chain hydroxylation). The patient then discontinues the secobarbital but continues to take the warfarin. How should the patient's warfarin dose be changed?

A.   The dose should be increased

B.   The dose should be decreased

C.   The dose should not be changed

5. For a drug that is eliminated by a first-order process, which parameter is dependent upon the dose?

A.   Clearance

B.   Elimination rate constant

C.   Steady-state plasma concentration

D.   Elimination half-life

E.   Time required to reach steady-state plasma concentration

6. A patient with seizures is started on phenytoin, 300 mg daily. Frequent plasma-level monitoring is done as part of a clinical study. After 5 days, phenytoin concentration in plasma is stabilized below the desired range, and the patient still has seizures. The dose is increased to 450 mg daily. It now takes 9 days for plasma levels to stabilize, and although seizures are controlled, the drug concentration in plasma is higher than predicted, and the patient shows signs of phenytoin toxicity. Which one of the following is the most likely explanation for the higher than predicted drug concentration?

A.   The enzymes that hydroxylate phenytoin are saturated, so its biotransformation is no longer a first-order process.

B.   There is accumulation of an active metabolite.

C.   Phenytoin is not very water soluble, so its distribution becomes limited at higher plasma concentrations.

D.   Phenytoin has induced the cytochrome P-450 enzymes, increasing its own biotransformation.

E.   The patient has a genetic inability to parahydroxylate phenytoin.

7. The total body clearance of theophylline in an adult weighing 70 kg is 48 mL/min. If theophylline is administered by continuous intravenous (IV) infusion at a rate of 60 mg/hour, the steady-state plasma concentration (Css) will be about

A.   1 mg/dL

B.   2 mg/dL

C.   5 mg/dL

D.   10 mg/dL

E.   20 mg/dL

8. A 53-year-old man has swollen ankles, shortness of breath, and fatigue upon mild exercise. He is observed to have severe pitting edema of the lower extremities, distended neck veins with prominent pulsation, a sinus tachycardia of 105 beats/min at rest, and a normal blood pressure. He is diagnosed as being in congestive heart failure. It is noted, however, that his renal function is relatively normal (creatinine clearance = 115 mL/min). If treatment is begun with oral digoxin (t½ = 36 hours) with a usual daily maintenance dose of 0.125 mg, how long should you wait before increasing the dose if his initial response appears inadequate?

A.   Approximately 2 hours

B.   Approximately 1 day

C.   Approximately 2 days

D.   Approximately 1 week

9. A patient with impaired renal function (creatinine clearance = 40 mL/min) is being treated for a urinary tract infection with a cephalosporin antibiotic. The drug is normally excreted unchanged by the kidneys with a clearance rate approximately equal to creatinine clearance (120 mL/min). The typical oral dose of the drug is 240 mg every 6 hours. Which of the following dosing regimens would be appropriate for this patient to achieve the same drug level as a patient without normal renal function?

A.   80 mg every 18 hours

B.   120 mg every 6 hours

C.   240 mg every 12 hours

D.   80 mg every 6 hours

E.   240 mg once a day

10. Which one of the following statements is true concerning the dose–response curves in the graph?

image

A.   Curves A, B, and C represent responses to weak agonists, with C being the most potent.

B.   Curve A represents the responses to a full agonist, and curves B and C represent the responses to the agonist in the presence of two concentrations of a competitive antagonist.

C.   Curves A, B, and C show that the three drugs are acting at different receptors because their potencies are different.

D.   Curve D shows the response to agonist A in the presence of a competitive inhibitor.

E.   Curve D represents an agonist with a high intrinsic efficacy, as the dose needed for a given effect is larger than that of agonists A, B, or C.

11. Which of the following provides information about the sensitivity of a population to a drug?

A.   Graded dose–response curve

B.   Quantal dose–response curve

C.   Therapeutic index

D.   Efficacy

12. An experiment was performed to determine the median effective dose required to produce hypnosis in 50% of the population (ED50) and the median lethal dose for 50% of the population (LD50) of a drug. The ED50 was found to be 1 mg. The LD50 was found to be 300 mg. What is the therapeutic index for this drug?

A.   < 1

B.   1

C.   3

D.   30

E.   300

13. The following table shows the drug dosages that produce a therapeutic effect (bronchodilation), a toxic effect (cardiac arrhythmia), and death in 1%, 50%, or 99% of patients. What is the median effective dose for 50% of the population (ED50)?

% of Patients Showing Effect

Dose Causing Bronchodilation (mg)

Dose Causing Cardiac Arrhythmia (mg)

Dose Causing Death (mg)

1%

1 mg

200 mg

2000 mg

50%

15 mg

750 mg

6000 mg

99%

200 mg

900 mg

9000 mg

A.   1 mg

B.   15 mg

C.   200 mg

D.   750 mg

E.   6000 mg

14. What is the median lethal dose for 50% of the population (LD50)?

A.   1 mg

B.   15 mg

C.   200 mg

D.   750 mg

E.   6000 mg

15. At a dose of 200 mg, what percentage of patients experienced an adverse effect?

A.   1%

B.   10%

C.   50%

D.   75%

E.   99%

16. If a patient overdoses on 9 g of the drug, what is the probability that the patient will die?

A.   1%

B.   10%

C.   50%

D.   75%

E.   99%

Answers and Explanations

1. B Bioavailability is the fraction of the administered dose of a drug that reaches the systemic circulation in an unchanged form (p. 3).

A. Plasma half-life is the time it takes for the drug level in the blood to decrease from its peak to one half of its peak.

C. Enterohepatic cycling occurs when conjugated drugs (mainly glucuronic acid derivatives) are actively secreted into bile, and unconjugated drugs are liberated in the small intestine by bacterial enzyme hydrolysis and reabsorbed into the portal circulation.

D. Biotransformation is the process by which drugs are metabolized to (usually) less active forms for excretion.

E. Biliary excretion occurs when drugs are delivered to the bile and then excreted.

2. B Vd = dose (mg)/plasma concentration (mg/L) = 500 mg/4.5 mg/L ≈ 100 L (p. 8).

3. C Toxic effects were observed at 0.5 hour, when the plasma concentration was 4.5 μg/mL, and a therapeutic effect lasted until 4 hours, at which time the level was 2.4 μg/mL. Halfway between these two is ~3.5 μg/mL. The apparent volume of distribution of the drug was calculated from the initial dose given intravenously and its plasma concentration after 30 minutes as follows: Vd = dose (mg)/plasma concentration (mg/L) = 500 mg/4.5 mg/L ≈ 100 L. The amount of drug (taken orally) needed to achieve a desired plasma concentration by rearrangement of this equation is: Dose = plasma concentration (mg/L) × Vd (L) = 3.5 mg/L × 100 L = 350 mg (p. 8).

4. B Induction of liver microsomal enzymes by secobarbital increases the metabolism of warfarin. Discontinuation of the secobarbital will lead to decreased microsomal enzyme activity, lower metabolism of warfarin, increased warfarin levels, and increased anticoagulant activity. Thus, the patient's dosage will have to be decreased to maintain the same degree of anticoagulant activity (p. 10).

5. C The only one of these that is dependent upon the dose is the steady-state plasma concentration, which equals [F × (D/T)]/CL, where F is bio-availability, D is dose, T is dosing interval, and CL is clearance (p. 17).

6. A Zero-order kinetics of elimination usually occur because the route of elimination has become saturated. In this case, phenytoin originally exhibited first-order kinetics when the drug concentration was below the maximum rate of the elimination process. As elimination was saturated, the time to steady-state peak level, as well as the achievement of a higher than predicted drug level, was observed. Only answer A addresses these findings; none of the other answers can explain them (p. 14).

7. B For drugs that are given by continuous IV infusion, the equation for calculating Css is Css = Ro/CL, where Ro is the infusion rate, and CL is clearance. Css = (60 mg/h)/(48 mL/min) = (1 mg/min)/(48 mL/min) = 0.02 mg/mL = 2 mg/dL (p. 15).

8. D The time to reach steady-state concentration (Css) is solely determined by the half-life (t½). Because it takes roughly four half-lifes for a drug to reach steady-state concentration (Css), for a drug with t½ = 36 hours, 4 × 36 hours = 144 hours, or ~1 week, is required to reach steady-state concentration (Css). Steady-state concentration coincides with the desired therapeutic concentration of a drug (p. 15).

9. D Css = [F × (D/T)]/CL, where Css is the steady-state concentration, F is bioavailability, D is dose, T is dosing interval, and CL is clearance. Because clearance is decreased in this patient to approximately one third of its normal value (= creatinine clearance), the maintenance dose must be decreased by one third or the dose interval increased 3-fold to achieve the same steady-state drug concentration (p. 17).

10. B Because a competitive antagonist competes with the agonist for binding to the receptor, more of the agonist drug is required to elicit a given response in the presence of a competitive antagonist. This results in the dose–response curve being shifted to the right (p. 25).

A. Curves A to C do not represent responses to a weak agonist because they all show 100% responses, which would not occur with a weak agonist. Also C is the least potent, not the most potent.

C. Variations in potency do not indicate that different receptors are affected.

D. A competitive antagonist does not reduce the maximal response, but instead increases the amount of agonist needed to obtain the same response.

E. Curve D, which does not reach a 100% response, represents a lower, not higher, efficacy for the agonist.

11. B A quantal dose–response curve plots the proportion of a population that responds to different concentrations of a drug (p. 25).

A. A graded dose–response curve plots the magnitude of a response as a function of the dose.

C. The therapeutic index is the ratio LD50/ED50, where LD50 is the drug dose that is lethal to 50% of the population and ED50 is the median effective dose for 50% of the population.

D. Efficacy is the maximum effect a given drug can produce.

12. E The therapeutic index is the ratio LD50/ED50. In this example, the therapeutic index would therefore be 300 (300/1), meaning that 300 times the median effective dose (ED50) would need to be given to produce a lethal effect for 50% of the population (p. 26).

13. B The ED50 is the dose that causes bronchodilation, in this case, in 50% of patients. This is achieved with a dose of 15 mg (p. 26).

14. E The LD50 is 6000 mg (p. 26).

15. A At a dose of 200 mg, only 1% of the patients experienced cardiac arrhythmia, the adverse effect (p. 26).

16. E At a dose of 9000 mg (or 9 g), 99% of patients will die (p. 26).